Abstract of Research Plan: Our primary objective is to develop technetium (99mTc) and fluorine ('*F) renal tracers with a clearance in humans at least equal to that of the clinical gold standard, ^'l or//zo-iodohippuran ('^'l-OIH) and approaching the clearance of para-aminohippurate (PAH). Such agents should replace, the current best tracer, 99mTc Tcinercaptoacetyltriglycine (99mTc-MAGS). As detailed in this submission, we have made excellent progress in spite of the challenges posed by the disruption of the worldwide supply of iTiolybdenum-99 (the parent isotope of 99mTc) due to a temporary shutdown of aging reactors. To address a future shortage of 99mTc and to take advantage of the inherently better resolution of PET and the widespread availability of PET scanners, we are extending our original specific aims to use innovative chemistry and ligand design to develop renal tracers labeled with 18F as well as 99mTc. Our secondary objective, which will be achieved in the process of accomplishing our first objective, is to enhance the understanding of technetium and rhenium (Re) chemistry and to develop novel ligands using our extension of the one-step (Al18F)2+ method for 18F labeling of peptides in aqueous solution. The basic chemistry research in this project will facilitate the development by others of new non-renal integrated and bifunctional. 99mTc and 18F diagnostic radiopharmaceuticals as well as beta-emitting 186Re and 188Re e therapeutic radiopharmaceuticals. We hypothesize that ligands based on the relatively new {Tc1(C0)3} core and structural analogues of the Al18FNODA-butyric acid complex offer the best avenue for continued breakthrough research and enhanced diagnostic accuracy. During the first 4 years of funding, we propose to continue to test these hypotheses and derivative hypotheses by using an innovative and iterative combination of chemical methods, efficient routes to versatile novel ligands, and streamlined animal models. Simultaneously, throughout years 1-5, the direction of these studies and generation of new hypotheses will be guided by our animal results, by results comparing new tracers with 131I-OIH in both normal human subjects and those with reduced renal function, and by results comparing new tracers with 99mTc-MAG3 in subjects with impaired renal function and suspected obstruction.